Partial Adherence to Antipsychotic Medication

Objective: Although many clinicians acknowledge the occurrence of adherence problems withmedication regimens among patients with schizophrenia, the problem shows no sign of improving.This may be because, in thinking about the issue,clinicians have tended to focus on patients whoopenly refuse or repeatedly discontinue treatment.While this description applies to only a minorityof patients, in our experience, full adherence israre; most patients are only partially adherent atbest. This article examines the issue of adherencebehavior in schizophrenia, focusing on the impactof partial adherence on treatment outcomes, particularly early in the course of illness. We alsoreview potential strategies for managing theproblem.Data Sources: Original research and reviewarticles published in English from 1980 to 2008were identified using the PubMed database, withthe search terms schizophrenia or psychosis combined with compliance, noncompliance, partialcompliance, adherence, nonadherence, or partialadherence.Study Selection: Articles were selected by theauthors on the basis of the hypotheses and/or datadescribed.Data Synthesis: Failure to adhere to medication as prescribed can have a major impacton the course of illness and treatment outcomesin patients with schizophrenia. Even relativelyshort gaps in medication coverage increase therisk of relapse. Problems with adherence arecommon early in the course of illness, whenthe consequences of relapse can be particularlydevastating.Conclusion: Clinicians in primary care andpsychiatric settings need to be vigilant for signsof adherence problems among their patients andto act when necessary to prevent or alleviate theconsequences of inadequate medication cover.Relapse prevention strategies, particularly forpatients with early psychosis, should includeensuring that medication lapses are minimizedor eliminated.Prim Care Companion J Clin Psychiatry 2009;11(4):147154doi:10.4088/PCC.08r00612 Copyright 2009 Physicians Postgraduate Press, Inc.

he failure by patients to take medication as prescribed is a phenomenon that is well known to clinicians in all medical specialties. Among patients withschizophrenia, adherence issues can severely limit theclinical improvement that is achievable with even the bestavailable treatments. There is, however, no evidence thatthe situation has improved over the last 30 years, and, despite the introduction of new medications with improvedtolerability profiles, poor adherence remains a problem.This may be because in both clinical research and day-today practice, adherence has often been portrayed as anall-or-nothing issue, with patients being regarded as eitheradherent or nonadherent. When considering interventionsfor adherence problems, clinicians have therefore tendedto focus on those patients who openly refuse or repeatedlydiscontinue treatment and are regarded as difficult-totreat cases. While this description applies to only a limitedproportion of patients, in our experience, full adherenceis rare. In reality, most patients are partially adherent tosome extent, but the focus on treatment discontinuationmay have led clinicians to discount partial adherence asan issue worthy of their attention, perhaps regarding it asinevitable and unavoidable. Unless clinicians appreciate

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the impact that relatively minor deviations from prescribed treatment regimens can have on treatment outcomes,1 they are unlikely to take the problem seriously orto devote sufficient time and attention to addressing suspected adherence problems among their patients.Notably, treatment adherence is considered to have amajor influence on achieving clinical remission.2 Failureto achieve remission is a predictor for poor prognosis,psychiatric complications, treatment resistance, and evendeath from medical comorbidities and suicide.3 Moreover,patients who fail to take their medication as prescribed areat a greatly increased risk of relapse.1,4,5 Given the devastating impact of psychotic relapse on the course of illness,relapse prevention strategies should encourage greaterawareness of the impact of partial adherence and shouldincorporate appropriate steps to minimize or eliminate theproblem, particularly during the early stages of the illness.This article examines the issue of adherence behaviorand its impact on treatment outcomes, with particular reference to early psychosis and first-episode patients, andprovides observations on suggested strategies for managing these issues in patients with schizophrenia.A search of the published literature from 1980 to 2008was performed using the PubMed search engine. Articleswritten in English (original research and reviews) wereidentified using the following keywords: schizophreniaor psychosis combined with compliance, noncompliance,partial compliance, adherence, nonadherence, or partialadherence. Additional references were identified throughcitations in relevant articles.NONADHERENCE AND PARTIAL ADHERENCE INSCHIZOPHRENIA: DEFINITIONS AND PREVALENCEIt has been known for many years that a substantialproportion of patients with schizophrenia do not take theirmedications as prescribed.6,7 Strictly speaking, nonadherence means failing to take any prescribed doses (althoughpatients who discontinue their medication after an initialperiod of adherence can also be correctly described asnonadherent). Full adherence (taking all doses as prescribed) represents the other end of the spectrum of adherence behaviors. The term partial adherence can be used todescribe all other patterns, from prolonged gaps in medication to infrequent lapses, including occasional missedor incorrect doses.79 In the past, the terms adherenceand compliance have been used interchangeably, althoughsome authors have used compliance to describe only theextent to which a patient takes his or her medication andhave used adherence to describe a broader concept thatencompasses lifestyle, habits, and diets and implies a collaborative attitude on behalf of the patient that leads toactive involvement in the therapeutic strategy. Compliance is now perceived to betray a paternalistic attitude toward the patient, however,10 and so is declining in use.

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In an early review, Young et al.11 found that reported

rates of adherence varied widely. This partly reflectsthe inconsistency between the definitions of adherence/partial adherence/nonadherence used in the different studies. In some, occasional missed doses were not regardedas nonadherence,6 while in others, patients were deemedto be adherent if they took as little as 70% of the prescribed medication.12 The studies cited below are limitedto those in which the definitions used were clearly stated.Differences between the populations studied and themethods used to quantify adherence behavior may alsoinfluence the estimates.Full adherence is uncommon in schizophrenia, as is thecase with most illnesses. Thus, Oehl et al.9 estimated thatonly about one third of patients with schizophrenia arefully adherent, with one third being partially adherent andone third nonadherent. Other authors suggest that at least50% of patients are not fully adherent with their medication at some time during their illness.13,14 With regardto the other extreme of adherence behaviortreatmentdiscontinuationYoung et al.11 concluded that up to40% of patients treated with conventional antipsychoticsstop taking their medication within a year.11 Other studieshave reported similar rates of discontinuation in outpatients (50%75%) during the 2 years following hospitaldischarge.15,16Partial adherence appears to be an even more pervasiveand insidious problem than treatment refusal or discontinuation; several studies have indicated very high rates ofpartial adherence among patients with schizophrenia. Forexample, McCombs et al.17 examined data for 2655 patients and concluded that one quarter had taken no antipsychotic drugs during the year of the study, but anotherquarter had delayed using antipsychotic drugs for 30 ormore days. Ninety-two percent had at least 1 disruption intreatment. In a study of 565 patients with schizophreniaor schizoaffective disorder, a similar proportion (90%)showed some level of partial adherence during a year offollow-up.18DETECTION OF ADHERENCE PROBLEMSAnother factor that may contribute to the variability inpublished rates of nonadherence and partial adherenceis that adherence behavior is not easy to detect and quantify, and all methods of detection have some drawbacks.First, even when asked directly, patients often deny beingpartially adherent or nonadherent.7 For example, in astudy of 68 patients with schizophrenia 3 months afterdischarge from hospital, the majority (55%) rated themselves as fully adherent, but, according to pill counts, only40% were adherent (> 80% of doses taken) and only 9%of these were fully adherent. Measurements of plasmadrug concentrations suggested an even lower adherencerate (23%).19 Valenstein et al.20 also found that patients

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overestimated their level of adherence compared with

their physicians, but physicians themselves have beenfound to overestimate their patients levels of adherence.15For example, in one 3-month study, none of the physicians rated their patients as nonadherent ( 4 on the Clinician Rating Scale) but an electronic Medication EventMonitoring System indicated that 48% had 70% dailyadherence.21Medication possession ratio information derived frompharmacy data can be a useful tool for identifying patientsrequiring assistance with adherence,22 but the use of thesedata in studies of adherence has major limitations.12,22 Although patients may collect their prescriptions on a regularbasis, they may not be taking the medication as prescribed.Other changes in clinical circumstances could causechanges in dosing patterns that are interpreted as being indicative of partial adherence.As partial adherence tends to be covert, accurate measurement is likely to be particularly difficult. A prospective study examining agreement among measures of adherence to oral antipsychotic medications in 52 outpatientswith schizophrenia found that, while pill count and electronic monitoring appeared to identify adherent patients(those who were at least 80% adherent), self-report andphysicians ratings failed to accurately differentiate between patients with or without adherence problems.23Although direct indicators (such as concentrations ofmedication in blood) are less subject to bias than indirectmeasures (self-reports, chart reviews, pill counts, or refillrates), every detection method has its limitations,24 andnone of the available methods are ideal.RECOGNITION OFADHERENCE PROBLEMS IN CLINICAL PRACTICEBeyond the research setting, the failure of physicians torecognize adherence problems among their patients canhave an important impact on prescribing behavior, patientoutcomes, and healthcare costs,23 but relatively few studieshave examined clinicians awareness of adherence problems in patients with schizophrenia. Giner et al.25 described the results of a survey of 330 Spanish psychiatristson their perceptions of adherence behavior among theirpatients. Nearly one half thought that patients should beclassed as nonadherent if they missed 10% to 25% of theirprescribed medication. Another third felt that 5% to 10%of missed doses should be regarded as nonadherence. Most(49%) thought that between one quarter and one half oftheir patients had adherence problems, but some (10%)saw adherence as a problem in up to three quarters of patients. Poor insight was identified as an important factorby 90% of physicians; the doctor-patient relationship wasalso thought to have an important influence. Eighty-fivepercent of physicians identified nonadherence as the maincause of relapse among their patients.

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A larger survey conducted in 11 European countries revealed that psychiatrists think that the majority of theirpatients have problems with adherence; two thirds (60%)were suspected of forgetting to take their medication atsome time in the previous month.26 Many patients (57%)were thought to be incapable of noticing a worsening intheir health after interrupting treatment, and a similar proportion (66%) were thought to lack awareness of their illness. About two thirds of patients were suspected of discontinuing their medication at some time because theyfelt better. Cognitive deterioration sufficient to affect adherence was identified in about 50%. Most were thoughtto need their family or others to remind them to take theirmedication but had life circumstances that were not conducive to adherence. Embarrassment or being upset athaving to take tablets every day was seen as a contributingfactor in two thirds. Similar results have been found inother national surveys.27,28Thus, when asked specifically, clinicians suspect manyof their patients have problems taking their medication asprescribed. The surveys did not ask whether they act ontheir suspicions, however, and the fact that poor adherence remains a common problem suggests that the issueis not being adequately addressed. It may be that clinicians do not fully appreciate the impact of gaps in treatment coverage on disease course and outcome. They mayassume that a chronic course of illness with multiple relapses is to be expected. In fact, as described below, formany patients with unsatisfactory outcomes, poor adherence is likely to be an important contributory factor.THE IMPACT OFNONADHERENCE AND PARTIAL ADHERENCEFailure to adhere to antipsychotic regimens is associated with exacerbation of psychotic symptoms,29 increased aggression against self and others,30 worse prognosis,31,32 increased use of inpatient and acute outpatientservices,33 and increased costs.34 Importantly, nonadherence to medication has been suggested to be the mostimportant modifiable factor contributing to psychotic relapse that leads to rehospitalization.14It is perhaps not surprising that major lapses or discontinuation of therapy can have a profound impact, butpartial adherence has also been shown to have importantconsequences. Using pharmacy refill and medical claimsdata for 4325 outpatients with schizophrenia, Weiden etal.1 found that the hospitalization rate was substantiallyhigher in patients who were less than 70% adherent thanin those with better adherence (23% vs. 13.8%, p < .001).A gap in medication coverage of as little as 1 to 10 daysalmost doubled the risk of hospitalization, showing thatrelatively minor deviations from treatment as prescribedcan have a major impact on outcomes. Another analysisof data from approximately 49,000 patients found that

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hospital admission was 2.4 times more likely in poorly

adherent patients (medication possession ratio, < 0.8)than in those with good adherence (medication possessionratio, 0.81.1).12 The admission rates were 23% and 10%,respectively. Importantly, partial adherence often remainsundetected until psychotic symptoms emerge or are exacerbated,35 but the longer patients fail to take their medication as prescribed, the greater is the impact on outcomes.36The negative consequences of partial adherence mayrange from increased stress to loss of functioning, breakthrough of symptoms, and, ultimately, relapse.In addition to the impact on patient outcomes, adherence behavior has also been shown to have an importanteffect on resource utilization and costs. Thus, Valensteinet al.12 found that poorly adherent patients spent moredays in hospital (33 days per year) than those with goodadherence (24 days per year), while Gilmer et al.37 reported that rates of psychiatric hospitalization were substantially lower among adherent (14%) than partiallyadherent (24%) or nonadherent (35%) patients. Hospitalcosts were also significantly lower in adherent patients,37and, in fact, nonadherence to antipsychotic drugs has beensuggested to be one of the most significant factors in increasing service costs.38 Marcus and Olfson39 calculatedthat improving adherence has the potential to reduceMedicaid inpatient care costs by more than $100 millionthrough reductions in acute-care admissions (12%) andinpatient treatment days (13%).NONADHERENCE AND PARTIAL ADHERENCEIN EARLY PSYCHOSIS: PREVALENCE AND IMPACTAdherence problems (both treatment discontinuationand partial adherence) appear to be common during theearly stages of schizophrenia7,4042 and to have importanteffects on course and outcome.43 First-episode patientsusually respond well to treatment44 but relapses are common,4 so improving adherence can be of long-term benefit.45 Robinson et al.46 found that 26% of first-episodepatients had stopped taking their medication (againstmedical advice) in the first year of treatment (43% haddiscontinued medication after recovery from their firstrelapse). In another early psychosis program, 39% ofpatients were nonadherent during the first year, but another 20% were described as poorly adherent (takingmedication irregularly).47 Focusing on partial adherence,Mojtabai et al.48 found 63% of first-admission patientsto have 1 or more gaps in their use of typical antipsychotics during the year after hospital discharge. Aboutone half of the gaps were for 30 days or more, most occurred soon after discharge, and 73% were initiated by thepatient.The importance of optimizing adherence early in thecourse of illness is indicated by a study of 104 firstepisode patients who had responded to treatment and

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were at risk for relapse.4 The risk of a first or second relapse when patients did not take medication was found tobe about 5 times greater than when they did take medication (initial relapse, hazard ratio = 4.89; second relapse,hazard ratio = 4.57). Moreover, in a naturalistic study of65 patients during the 2 years after hospital discharge after a first admission for psychosis, those with poor adherence (at least 1 interruption in medication in 2 years,against medical advice) were 5 times more likely to havean episodic course and were more likely to have been readmitted (the risk of compulsory readmission was increased 3-fold).49RISK FACTORS AND STRATEGIES FORADDRESSING ADHERENCE PROBLEMSGiven the impact of adherence behavior throughoutthe course of illness, we consider it essential for cliniciansto be vigilant in recognizing adherence problems amongtheir patients and to act when necessary to prevent or alleviate the consequences of inadequate medication cover.Clinicians first need to be aware of the factors that canlead to adherence problems. On the basis of our experience, we would emphasize the impact of distressing sideeffects on adherence behavior; other important obstaclesinclude cost and access, the use of complicated treatmentregimens, and the impact of cognitive impairment. In thissection, we review the published research on risk factorsand examine some strategies that have been proposed toaddress the problem.Several authors have identified what Tacchi and Scott50described as a predictable checklist of features associated with nonadherence, including being young, male,and unemployed or socially isolated; a past history ofnonadherence; and, possibly, current use of illicit substances. Based on a review of 39 studies, however, Lacroet al.24 found no association between adherence and eitherage or gender. The factors that were consistently associated with adherence problems were poor insight, negativeattitude or subjective response to medication, previousnonadherence, substance abuse, short illness duration, inadequate discharge planning or aftercare environment,and a poor therapeutic alliance. Surprisingly, the severityof psychotic symptoms or medication side effects did nothave notable effects. To date, few studies have adequatelyquantified the relative importance of the different risk factors, but, in a recent review, Narasimhan et al.51 concludedthat symptomatology, cognitive function, disease insight,and presence of substance abuse were the most importantfeatures.A similar range of factors have been proposed to influence adherence behavior during the early stages of illness.For example, in first-episode patients, Robinson et al.46found that poor premorbid cognitive functioning was animportant predictor of treatment discontinuation during

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the first year of therapy. After the first relapse, discontinuation was more likely when Parkinsonian side effects werepresent but less likely in patients with better executivefunction. In another first-episode study, McEvoy et al.52found that lack of insight was an important risk factor,while Kampman et al.53 concluded that younger age,male sex, lack of social activities, presence of side effects, and high Positive and Negative Syndrome Scale(PANSS) total and low PANSS positive scores were allpredictors of nonadherence in first-episode patients. Similarly, Coldham et al.47 found that nonadherent earlypsychosis patients were younger, had an earlier onset, andlacked a family member with involvement in the treatmentplan. In first-episode patients, Verdoux et al.49 found thatlow occupational status, alcohol misuse, and the severityof delusions and suspiciousness were all predictors of pooradherence. There are many contradictory findings, however50; this is probably because studies have tended toexamine the impact of each risk factor in isolation. One recent study evaluating the relative impact of several putative risk factors54 concluded that early psychosis patientswho show poor adherence tend to have issues with trustingauthority (childhood trauma, severity of symptoms, and apoor therapeutic alliance were also found to be important).A post hoc analysis of data from German patients in theSchizophrenia Outpatient Health Outcomes study foundthat adherence to antipsychotic medication was stronglyassociated with subjective well-being; patients with lesssevere symptoms (including extrapyramidal symptoms)were more adherent.55 The causal relationships are unproven; patients who are more adherent might be expectedto be less symptomatic. Conversely, incomplete control ofsymptoms or persistence of side effects could reduce wellbeing and so act as a disincentive for patients to continuetaking their medication as prescribed. In this regard, it hadbeen assumed that the introduction of the atypical antipsychotic drugs would lead to improvements in adherence,56given their generally favorable tolerability profiles compared with the typical antipsychotics. The results of studies comparing adherence with older and newer antipsychotic drugs are, however, inconclusive and conflicting,and adherence rates with atypical drugs remain lowerthan had been hoped. For example, using pharmacy refillrecords to quantify adherence in outpatient veterans,Dolder et al.57 found that patients receiving atypical antipsychotics were without medication for 4 days per monthon average compared with 7 days per month for those receiving typical antipsychotics (and as previously mentioned, this level of partial adherence can have importanteffects on outcomes). More recently, in the CUtLASSstudy, no differences in adherence were found betweenpatients treated with first- and second-generation antipsychotic drugs.58 Problems with adherence therefore persist,despite the availability of drugs with improved side-effectprofiles.

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disruptive to patients daily routines, thus increasing therisk of missed doses or discontinuation of treatment.51Long-acting neuroleptics can address all-cause discontinuation and poor adherence,59 and treatment guidelines(e.g., American Psychiatric Association, SchizophreniaPatient Outcomes Research Team, Texas Medication Algorithm Project) strongly recommend using depot formulations for patients who are noncompliant with oralagents, but clinicians seem reluctant to modify their practice, even for patients who are overtly nonadherent. Forexample, Valenstein et al.60 found that almost one half(49%) of 1307 veterans with schizophrenia or schizoaffective disorder were known to have been nonadherent inthe previous year, yet only 18% were receiving depotneuroleptics. They concluded that there are barriers toimplementing the recommendations but noted that, untilrecently, only typical neuroleptics were available in longacting formulations. Others have suggested that longacting formulations of atypical neuroleptics represent amore promising solution.59,61 In one 12-month trial oflong-acting risperidone, less than 2% of patients discontinued due to adherence issues, and only 18% had to bereadmitted to hospital.62 No direct comparisons betweenlong-acting risperidone and depot typical neuroleptics areavailable, but patients whose symptoms were stable during treatment with typical depots did show improvementsafter switching to long-acting risperidone.63 Patientsswitched from oral risperidone also showed improvements,64 presumably due to continuity of medicationdelivery and elimination of covert partial adherence. Indaily clinical practice, the use of a long-acting agentmeans that adherence problems cannot be hidden; as soonas the patient misses an injection, the clinician can takeactions to address the issue and to involve the family andother caregivers.51 Historically, long-acting agents (particularly depot formulations of typical antipsychoticagents) have tended to be reserved for more chronically illpatients with a clear history/high risk of nonadherence,but some authors have suggested a role for such agentsearlier in the course of illness, including for first-episodepatients.65 The feasibility of this approach (i.e., its acceptability to patients) is indicated by the finding that 73% offirst-episode patients who were stable after treatment withan oral atypical antipsychotic accepted a recommendationof changing to a long-acting atypical agent when this wasdiscussed as part of an integrated treatment plan.66Relatively few studies of adherence behavior have examined the impact of personal beliefs and attitudes or ofcontextual factors such as family environment, but in onestudy of first-episode patients that did evaluate attitudinaland clinical factors, both negative attitudes to medicationand a lack of insight or awareness of illness were significant predictors of poor adherence.67 Other authors havesuggested that a negative attitude to medication may be

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an important factor among many patients with schizophrenia.50 Patients may refuse to accept the need for medication, particularly during the early stages of illness whenthey have experienced only 1 or 2 psychotic episodes.7For young people, the idea of taking medication for therest of their life can be a worrying prospect. They mayalso regard the need for daily medication as a sign ofweakness or inferiority (a perception that can be reinforced by societal stigma), and it may be difficult for themto understand the benefits of medication, particularly ifthey regard their condition as temporary and not the resultof an illness. They may also need reassurance that themedication is their insurance against symptoms recurring.All these considerations highlight the importance of establishing a strong therapeutic alliance, and, in one study,nonadherence after a recent acute hospitalization wasfound to be predicted by poor therapeutic alliances withstaff as well as refusal of families to be involved in treatment.33 In contrast, the presence of a positive therapeuticalliance meant that patients took less time to switch frombeing nonadherent to adherent.68No single factor is likely to explain the adherence behavior of an individual, and, among schizophrenia patients as a group, a number of different factors appears tobe important.5,14,69 It has been suggested that interventionsfor adherence problems are particularly relevant to patients with a history of relapse related to poor adherence,to those with limited awareness of their disease, and tothose with comorbid substance abuse.28 However, formost patients, adherence issues are multifactorial; thereis unlikely to be a single answer to the problem. An individualized approach is needed, based on an evaluationof the factors or combinations of factors likely to havemost influence on the individuals adherence behavior.For example, in patients with first-episode psychosis,70 itwas reported that a structured early intervention programbased on specifically adapted interventions (includingcognitive-behavioral therapy, medication management,vocational support, and family interventions) significantly reduced treatment discontinuation compared withthat achieved by standard community services.Regular assessment of adherence behavior is essential,but when issues with adherence do become apparent, clinicians may feel that they do not have the time or resources to address the problem adequately. In addition,there is only a limited evidence base on the effectivenessof specific interventions. Studies tend to involve complexapproaches, comprising combinations of more convenientcare, information, counseling, reminders, self-monitoring,reinforcement, family therapy, and other forms of enhanced supervision or attention.71 Most interventions havebrought only limited improvements, and other approachesare needed.72 Interventions that employ educational andbehavioral strategies are more likely to be successful thanpurely didactic approaches.5,50,73 Consequently, Tacchi and

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Scott50 suggested a number of steps toward addressing

problems of nonadherence and partial adherence thatcould be used by any mental health professional withoutadditional training. These include investing time in thedevelopment of a strong therapeutic alliance; developinga shared understanding of patients problems; establishingthe acceptability and manageability of possible interventions (before prescribing an evidence-based treatment);establishing positive reasons for accepting treatment, forexample, by linking adherence to personal goals (suchas returning to work); maintaining vigilance for signs ofambivalence about treatment; checking repeatedly thatpatients understand the nature of the disorder and therationale for medication; and incorporating simple interventions for nonadherence into routine clinical practice(involving education, behavioral techniques and interventions, and cognitive techniques).50 Other practical stepsthat could be considered by clinicians include the use ofonce-daily dosing regimens for oral medications togetherwith various types of medication calendars, diaries or organizers, and electronic reminders and alarms as well aspill dispensers or blister packs.CONCLUSIONSProvided that they receive optimal early intervention,patients experiencing their first psychotic episode havegood prospects for improved outcome, including longterm remission.7477 On the other hand, the risk of relapseis high, particularly early in the course of illness,4 and theconsequences of relapse can be devastating in terms oflost educational, occupational, and social developmentopportunities. Adherence problems leading to relapsecan therefore have profound detrimental consequencesfor long-term outcomes. A psychotic relapse is a seriousmedical emergency and should be recognized as such byclinicians. Relapse-prevention strategies should includeproviding the most appropriate medication and ensuringthat medication lapses are minimized or eliminated.Further research involving longer-term studies of interventions aimed at improving adherence among individuals with schizophrenia is clearly warranted, as fewstudies have assessed whether positive effects of interventions are maintained in the long term. More methodologically rigorous research on the economic impact of nonadherence and the cost-effectiveness of strategies forenhancing adherence is also needed.Drug name: risperidone (Risperdal and others).